Problem: The function of the immune system is to distinguish self from non-self. When self-tolerance is lost, auto-immunity ensues. Systemic lupus erythematosus is a prototypic auto-immune disease, where loss of tolerance to nuclear antigens leads to a plethora of autoimmune pathology. Yet, little is known about which tolerance check points or mechanisms are actually breached in this disease. Parallel advances in the fields of B- cell tolerances, and genetics of autoimmunity, now allow us to investigate this in a systematic manner. Research Design: The use of immunoglobulin transgenics allows us to assess the integrity of B-cell tolerance at successive check points: deletion, receptor-edition, follicular exclusion, and anergy. Also, the availability of B6 congenic strains bearing individual lupus susceptibility intervals, allows us to evaluate the impact of each of these loci on B-cell tolerance, in a systematic way. This proposal will focus on two such potent loci, originally derived from the NZM2410 lupus strain: Sle1, which is responsible for triggering a strong anti-nuclear humoral response, and Sl32, which leads to spontaneous B-cell hyperactivity. By crossing DNA-specific, or lysozyme-specific immunoglobulin transgenes into these congenic backgrounds, we plan to study how Sle1 and Sle2 impact B-cell tolerance, to these two antigens. Significance: These experiments will tell us if the different lupus susceptibility loci breach B-cell tolerance in a global, or (nuclear) antigen-specific manner. Appreciating how the lupus genes tip the delicate balance from tolerance, towards flagrant auto-aggression, together with their actual identification, will enrich our understanding of lupus and humor autoimmunity, and pave the way towards more rational and effective therapy.